Cutaneous Nociception Evoked by 15-delta PGJ2 via Activation of Ion Channel TRPA1

Author:

Cruz-Orengo Lillian1,Dhaka Ajay2,Heuermann Robert J1,Young Timothy J1,Montana Michael C1,Cavanaugh Eric J3,Kim Donghee3,Story Gina M1

Affiliation:

1. Washington University Pain Center, Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63130, USA

2. Department of Cell Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA

3. Department of Physiology, Rosalind Franklin University of Medicine and Science The Chicago Medical School, North Chicago, IL, 60064, USA

Abstract

Background: A number of prostaglandins (PGs) sensitize dorsal root ganglion (DRG) neurons and contribute to inflammatory hyperalgesia by signaling through specific G protein-coupled receptors (GPCRs). One mechanism whereby PGs sensitize these neurons is through modulation of “thermoTRPs,” a subset of ion channels activated by temperature belonging to the Transient Receptor Potential ion channel superfamily. Acrid, electrophilic chemicals including cinnamaldehyde (CA) and allyl isothiocyanate (AITC), derivatives of cinnamon and mustard oil respectively, activate thermoTRP member TRPA1 via direct modification of channel cysteine residues. Results: Our search for endogenous chemical activators utilizing a bioactive lipid library screen identified a cyclopentane PGD2 metabolite, 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), as a TRPA1 agonist. Similar to CA and AITC, this electrophilic molecule is known to modify cysteines of cellular target proteins. Electophysiological recordings verified that 15d-PGJ2 specifically activates TRPA1 and not TRPV1 or TRPM8 (thermoTRPs also enriched in DRG). Accordingly, we identified a population of mouse DRG neurons responsive to 15d-PGJ2 and AITC that is absent in cultures derived from TRPA1 knockout mice. The irritant molecules that activate TRPA1 evoke nociceptive responses. However, 15d-PGJ2 has not been correlated with painful sensations; rather, it is considered to mediate anti-inflammatory processes via binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ). Our in vivo studies revealed that 15d-PGJ2 induced acute nociceptive responses when administered cutaneously. Moreover, mice deficient in the TRPA1 channel failed to exhibit such behaviors. Conclusion: In conclusion, we show that 15d-PGJ2 induces acute nociception when administered cutaneously and does so via a TRPA1-specific mechanism.

Publisher

SAGE Publications

Subject

Anesthesiology and Pain Medicine,Cellular and Molecular Neuroscience,Molecular Medicine

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